title: Analysis of primary resistance mutations to HIV-1 entry inhibitors in therapy naive subtype C HIV-1 infected mother-infant pairs from Zambia.
abstract: BACKGROUND
  Small molecular CCR5 inhibitors represent a new class of drugs for treating HIV-1 infection. The evaluation of the primary resistance mutations associated with entry inhibitors during HIV-1 perinatal transmission is required because they may have a profound impact on the clinical management in MTCT.
  
  
  OBJECTIVE
  To evaluate the primary resistance mutations to maraviroc and vicriviroc during perinatal transmission and analyze the sensitivity of Env derived from mother-infant pairs to maraviroc.
  
  
  METHODS
  Nine MIPs infected by subtype C HIV-1 were recruited to analyze the prevalence and transmission of primary resistance mutations to maraviroc and vicriviroc. Moreover, Env derived from six MIPs were employed to construct provirus clones and to analyze the sensitivity to maraviroc.
  
  
  RESULTS
  Mutations A316T, conferring partial resistance to maraviroc, T307I and R315Q, both conferring partial resistance to vicriviroc are prevalent in mother and infant cohorts, indicating the transmission of primary resistance mutations during HIV-1 perinatal transmission. However, the mutations of acutely infected mothers seem to directly transmit to their corresponding infants, while some mutations at low frequency of chronically infected mothers would be lost during transmission. Moreover, provirus clones derived from acutely infected MIPs are less susceptible to maraviroc than those from chronically infected MIPs.
  
  
  CONCLUSIONS
  Our study suggests that the transmission mode of primary resistance mutations and the sensitivity to maraviroc are dependent on infection status of MIPs either acutely or chronically infected. These results may indicate that higher dose of maraviroc could be needed for treatment of acutely infected MIPs compared to chronically infected MIPs.
authors.affiliation: Laboratory of Medical Molecular Virology, School of Medicine, Nankai University, Tianjin, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Guo
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Charles
authors.initials: C
authors.lastname: Wood
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Kong
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D003001:Cloning, Molecular; D003510:Cyclohexanes / Q000494:pharmacology; D024882:Drug Resistance, Viral; D005260:Female; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000635:transmission / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D000077592:Maraviroc; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010879:Piperazines / Q000494:pharmacology; D011247:Pregnancy; D011743:Pyrimidines / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D014230:Triazoles / Q000494:pharmacology; D055815:Young Adult; D015024:Zambia; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D003510:Cyclohexanes; D023581:HIV Fusion Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D014230:Triazoles; D054299:env Gene Products, Human Immunodeficiency Virus; D000077592:Maraviroc; C486781:vicriviroc
keywords: DMEM; DRAM; Dulbecco's Modified Eagle's Medium; FBS; HIV-1; IFA; MIP; MTCT; Maraviroc; NNRTI; PBMC; Primary resistance; Subtype C; Vicriviroc; drug resistance-associated mutation; fetal bovine serum; human immunodeficiency virus type 1; immunofluorescence assay; mother-to-child transmission; mother–infant pair; non-nucleoside reverse transcriptase inhibitor; peripheral blood mononuclear cells